US12391704B2 - Method for synthesizing decursin derivative - Google Patents

Method for synthesizing decursin derivative

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Publication number
US12391704B2
US12391704B2 US17/787,937 US202017787937A US12391704B2 US 12391704 B2 US12391704 B2 US 12391704B2 US 202017787937 A US202017787937 A US 202017787937A US 12391704 B2 US12391704 B2 US 12391704B2
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decursin
solution
mixing
compound
reaction solution
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US20230063754A1 (en
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Min Ju Kim
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PRG S&Tech Inc
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PRG S&Tech Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present disclosure relates to a novel method for synthesizing a decursin derivative.
  • HGPS Hutchinson Gilford progeria syndrome
  • HGPS is a very rare autosomal dominant genetic disease caused by a silent mutation of G608G in lamin A (LMN A).
  • the mutation causes creation of a new cleavage donor site and production of progerin (Prg) which is a product of a selective cleavage site from which 50 amino acids in the C-terminal domain of lamin A are deleted.
  • Prg progerin
  • progerin induces morphological changes such as irregularity in nuclear membranes or a decrease in nuclear-cytoplasmic lamin A, and suppression of progerin expression also induces a decrease in nuclear transformation. Thus, progerin is determined as a major factor of HGPS.
  • An object of the present disclosure is to provide a method for synthesizing a novel decursin derivative, capable of increasing the yield of a decursin derivative compound and enabling mass production.
  • example embodiments of the present disclosure provide a method for synthesizing a decursin derivative, the method including (I) preparing a solution by mixing cinnamyl bromide and an N-methyl-2-pyrrolidone (NMP) solvent; (II) preparing a solution by mixing decursinol, a tetrahydrofuran (THF) solvent, and sodium hydride (NaH); and (III) obtaining a decursin derivative represented by Chemical Formula 1 by mixing the solutions prepared in (I) and (II).
  • NMP N-methyl-2-pyrrolidone
  • THF tetrahydrofuran
  • NaH sodium hydride
  • FIG. 1 is a diagram showing NMR results of a decursin derivative synthesized according to an example embodiment of the present disclosure.
  • the present inventors were able to increase the yield of obtained decursin derivative compounds when the synthesis was performed using an N-methyl-2-pyrrolidone (NMP) solvent, a tetrahydrofuran (THF) solvent, and sodium hydride (NaH) in the process of synthesizing a decursin derivative from cinnamyl bromide and decursinol, and completed the present disclosure by identifying an optimal novel synthesis method deriving a high yield of 80% or more after an additional recrystallization process.
  • NMP N-methyl-2-pyrrolidone
  • THF tetrahydrofuran
  • NaH sodium hydride
  • the cinnamyl bromide and NMP are included in a weight ratio of 1:(5 to 10), and a solution may be prepared by mixing cinnamyl bromide and NMP and then stirring the mixture at 15-25° C.
  • the decursinol, THF, and NaH are included in a weight ratio of (5 to 10):(50 to 100):1, and after preparing a solution by mixing the decursinol and THF and stirring the same at 15-25° C., addition of NaH is followed at ⁇ 5-5° C. for preparation.
  • the method may further include recrystallizing the obtained decursin derivative.
  • the recrystallizing may include preparing a reaction solution by mixing acetone with the obtained decursin derivative (first step); preparing a reaction solution by mixing a seed with the reaction solution of the first step (second step); mixing the reaction solution of the second step with isopropyl alcohol and concentrating the mixture under reduced pressure (third step); and obtaining a decursin derivative by filtering and drying the solution concentrated under reduced pressure in the third step (fourth step).
  • the seed is a decursin derivative product having a purity of 99.5% or more and 0.10% or less of individual related substances, facilitating crystallization when the seed is used in the crystallization process. In addition, it is possible to remove the related substances while control of polymorph is easy.
  • the yield of the decursin derivative compound according to an example embodiment of the present disclosure becomes significantly lowered or mass production is hardly possible, which may be cost ineffective.
  • the (7S)-(+)-8,8-dimethyl-7-(3-phenyl-allyloxy)-7,8-dihydro-6H-pyrano [3,2-g]chromen-2-one (SLC-D011) compound which is a decursin derivative synthesized according to an example embodiment of the present disclosure may effectively be used in the treatment of aging-related diseases such as Hutchinson Gilford progeria syndrome (HGPS) and Werner syndrome, used as a cosmetic composition for preventing or ameliorating wrinkles since the compound is able to increase collagen production in skin cells, and also applied to a pharmaceutical composition and health functional food for the prevention and treatment of atopic dermatitis.
  • HGPS Hutchinson Gilford progeria syndrome
  • Werner syndrome used as a cosmetic composition for preventing or ameliorating wrinkles since the compound is able to increase collagen production in skin cells, and also applied to a pharmaceutical composition and health functional food for the prevention and treatment of atopic dermatitis.
  • the Solution 1 was added to the Solution 2 while maintaining the internal temperature at ⁇ 5-5° C., followed by stirring for at least 10 hours.
  • reaction solution was heated at 80-85° C. for 2 hours, stirred at 45-50° C. for 2-4 hours, and then cooled after stirring at ⁇ 5-5° C. for 4-8 hours.
  • the product was filtered using a centrifuge filter, and the filtered product was washed with cooled toluene ( ⁇ 5-5° C., 27 kg), followed by drying at 35-40° C. until the residual toluene becomes 0.5% or less.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
US17/787,937 2019-12-24 2020-11-06 Method for synthesizing decursin derivative Active 2042-08-22 US12391704B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
KR1020190174080A KR102283391B1 (ko) 2019-12-24 2019-12-24 데커신 유도체의 신규 합성방법
KR10-2019-0174080 2019-12-24
PCT/KR2020/015492 WO2021132872A1 (ko) 2019-12-24 2020-11-06 데커신 유도체의 신규 합성방법

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US20230063754A1 US20230063754A1 (en) 2023-03-02
US12391704B2 true US12391704B2 (en) 2025-08-19

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US (1) US12391704B2 (de)
EP (1) EP4083045B1 (de)
JP (1) JP7377981B2 (de)
KR (1) KR102283391B1 (de)
CN (1) CN114867728B (de)
WO (1) WO2021132872A1 (de)

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KR102705323B1 (ko) * 2021-10-06 2024-09-12 (주)피알지에스앤텍 데커신 유도체의 신규 합성방법

Citations (6)

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Publication number Priority date Publication date Assignee Title
KR20090037185A (ko) 2007-10-11 2009-04-15 박용진 (-)-데쿠르신 유도체를 포함하는 아토피성 피부염 질환의치료 및 예방용 조성물
KR20100008808A (ko) 2008-07-17 2010-01-27 박용진 신규 (+)-데쿠르신-에테르 유도체를 포함하는 아토피성피부염 질환의 치료 및 예방용 조성물
JP2016522821A (ja) 2013-05-08 2016-08-04 フイルメニツヒ ソシエテ アノニムＦｉｒｍｅｎｉｃｈ Ｓａ プロ香気化合物
KR20180019490A (ko) 2016-08-16 2018-02-26 지이-히타치 뉴클리어 에너지 어메리카스 엘엘씨 코어 슈라우드를 검사하기 위한 원격 작동 차량, 시스템, 및 방법
WO2018199633A1 (ko) 2017-04-25 2018-11-01 (주)피알지에스앤텍 데커신 유도체를 유효성분으로 함유하는 노화 관련 질환 예방 또는 치료용 약학조성물
KR20180119490A (ko) 2017-04-25 2018-11-02 (주)피알지에스앤텍 데커신 유도체를 유효성분으로 함유하는 노화 관련 질환 예방 또는 치료용 약학조성물

Patent Citations (7)

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Publication number Priority date Publication date Assignee Title
KR20090037185A (ko) 2007-10-11 2009-04-15 박용진 (-)-데쿠르신 유도체를 포함하는 아토피성 피부염 질환의치료 및 예방용 조성물
KR20100008808A (ko) 2008-07-17 2010-01-27 박용진 신규 (+)-데쿠르신-에테르 유도체를 포함하는 아토피성피부염 질환의 치료 및 예방용 조성물
JP2016522821A (ja) 2013-05-08 2016-08-04 フイルメニツヒ ソシエテ アノニムＦｉｒｍｅｎｉｃｈ Ｓａ プロ香気化合物
KR20180019490A (ko) 2016-08-16 2018-02-26 지이-히타치 뉴클리어 에너지 어메리카스 엘엘씨 코어 슈라우드를 검사하기 위한 원격 작동 차량, 시스템, 및 방법
WO2018199633A1 (ko) 2017-04-25 2018-11-01 (주)피알지에스앤텍 데커신 유도체를 유효성분으로 함유하는 노화 관련 질환 예방 또는 치료용 약학조성물
KR20180119490A (ko) 2017-04-25 2018-11-02 (주)피알지에스앤텍 데커신 유도체를 유효성분으로 함유하는 노화 관련 질환 예방 또는 치료용 약학조성물
US20200048274A1 (en) 2017-04-25 2020-02-13 Prg S&Tech Inc. Pharmaceutical composition for preventing or treating aging-related diseases containing decursin derivative as active ingredient

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Title
Aldrich , Aldrich Catalogue, 1998-1999, pp. 1154 and1570). (Year: 1999). *
International Search Report for PCT/KR2020/015492 mailed Feb. 23, 2021 from Korean Intellectual Property Office.
Japan Chemical Society, Experimental Chemistry Guide Book, Marzen Co., Ltd., pp. 130 to 131.
Lee, K. et al., "Synthesis of (S)-(ϕ)-decursin and its analogues as potent inhibitors of melanin formation in B16 murine melanoma cells", European Journal of Medicinal Chemistry, vol. 45, Issue 12, Dec. 2010, pp. 5567-5575.
Lee, W. et al., "Suppressive activities of KC1-3 on HMGB1-mediated septic responses", Biochemical Pharmacology, vol. 163, May 2019, pp. 260-268.
Office Action of Japanese Patent Application No. 2022-539009 mailed Jun. 9, 2023.

Also Published As

Publication number Publication date
KR20210081793A (ko) 2021-07-02
EP4083045B1 (de) 2023-12-13
EP4083045A1 (de) 2022-11-02
CN114867728B (zh) 2024-07-23
EP4083045A4 (de) 2023-05-24
US20230063754A1 (en) 2023-03-02
JP7377981B2 (ja) 2023-11-10
WO2021132872A1 (ko) 2021-07-01
CN114867728A (zh) 2022-08-05
JP2023508962A (ja) 2023-03-06
KR102283391B1 (ko) 2021-07-30

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